Beneficial effects of carotenoid-rich fruits and vegetables on cancer risk have been found in many epidemiological studies. In contrast, clinical intervention trials conducted to determine the effect of Beta-carotene (B- carotene) supplementation on the incidence of lung cancer in smokers or asbestos-exposed workers found a negative effect. Several studies indicate that the carcinogenic response to high dose B-carotene supplementation reported in the human intervention trials may be related to the dosage used and/or the instability of the B-carotene in the free radical-rich environment of the lungs of cigarette smokers. Recent supporting evidence for a protective role of lycopene against the risk of lung and prostate cancer has been reported in both human epidemiologic studies and animal studies. However, an understanding of the mechanistic basis for the possible chemopreventive efficacy of lycopene under well- controlled experimental conditions is needed. More specifically, it is not known whether lycopene, which is similar to B-carotene in chemical structure, has organ specific functions; i.e., lycopene might protect against prostate cancer but may interact with tobacco smoke to produce an unexpected adverse effect on lung cancer. In the proposed study, the researchers will investigate the mechanistic basis for the chemopreventive efficacy of lycopene under a variety of different circumstances (e.g., at varying doses, with and without exposure to tobacco smoke, lung versus prostate) in the ferret model. They will determine if there is a dose-dependent relationship between lycopene intake and oxidative stress in both plasma and tissue (lung and prostate). They will determine the effectiveness of lycopene at both a physiologic (low) and a pharmacologic (high) dose as an antiproliferative or proliferative agent in the smoke- exposed ferret by examining cell proliferation, expression of p53 tumor suppressor and its target gene, and apoptosis in lung. In addition, they will examine the formation of oxidative metabolites of lycopene in vitro in the tissue of smoke-exposed versus non smoke-exposed lung and prostate tissues of ferrets. These studies will provide important information for the potential future use of lycopene as cancer preventive nutrient at different tissue sites and the knowledge of possible adverse effects with tobacco.